Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently inhibit feline immunodeficiency virus replication
Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently inhibit feline immunodeficiency virus replication
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DOI：
10.1128/jvi.73.8.6346-6352.1999
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发表时间：
1999-08-01
影响因子：
5.4
通讯作者：
Schols, D
中科院分区：
文献类型：
--
作者：
Egberink, HF;De Clercq, E;Schols, D
双环芳烃是一种低分子的抗人类免疫缺陷病毒(HIV)药物，已被证明是有效的和选择性的CXC趋化因子受体4(CXCR4)拮抗剂。在这里，我们证明，当在克兰德尔猫肾(CRFK)细胞中进行评估时，双壳类化合物是猫免疫缺陷病毒(FIV)复制的有效抑制剂。在该细胞体系中，一系列双环素衍生物对FN的半数抑制浓度(IC(50)S)与HIV-1IIIB在人CD_4(+)MT-4T细胞系中复制的抑制浓度相当。双壳类化合物也能够阻止FIV在猫胸腺细胞中的复制，尽管浓度高于CRFK细胞。1-1‘-[1，4-phenylene-bis(methylene)]-bis(1，4，8，11-tetraazacyclotetradecane)，在猫胸腺细胞中的活性(IC(50)，62 ng/ml)仅为CRFK细胞(IC(50)，14 ng/ml)的四倍。AMD2763，1，1’-propylene-bis(1，4，8，11-tetraazacyclotetradecane)，是一种效力较弱的CXCR4拮抗剂，在猫胸腺细胞中几乎对FIV无效(IC(50)，>；66.5微克/毫升)，而对CRFK细胞有明显活性(IC(50)，0.9微克/毫升)。CXC趋化因子基质细胞衍生因子1a对CRFK细胞有抗FIV活性(IC(50)，200 ng/ml)，对猫胸腺细胞无抗FIV活性(IC(50)，2.5ug/ml)。当对初代FIV分离株进行猫胸腺细胞药物敏感性评估时，双壳类化合物AMD3100及其锌(2+)络合物AMD3479对所有6株初代分离株都有同等效力的抑制作用。FN对双壳类的明显敏感性表明，FIV主要利用猫科动物的CXCR4进入其靶细胞。
Bicyclams are low-molecular-weight anti-human immunodeficiency virus (HIV) agents that have been shown to act as potent and selective CXC chemokine receptor 4 (CXCR4) antagonists. Here, we demonstrate that bicyclams are potent inhibitors of feline immunodeficiency virus (FIV) replication when evaluated in Crandell feline kidney (CRFK) cells. With a series of bicyclam derivatives, 50% inhibitory concentrations (IC(50)s) against FN were obtained in this cell system that were comparable to those obtained for HIV-1 IIIB replication in the human CD4(+) MT-4 T-cell line. The bicyclams were also able to block FIV replication in feline thymocytes, albeit at higher concentrations than in the CRFK cells. The prototype bicyclam AMD3100, 1-1'-[1,4-phenylene-bis(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane), was only fourfold less active in feline thymocytes (IC(50), 62 ng/ml) than in CRFK cells (IC(50), 14 ng/ml), AMD2763, 1,1'-propylene-bis(1,4,8,11-tetraazacyclotetradecane), which is a less potent CXCR4 antagonist, was virtually inactive against FIV in feline thymocytes (IC(50), >66.5 mu g/ml), while it was clearly active in CRFK cells (IC(50), 0.9 mu g/ml). The CXC chemokine stromal-cell-derived factor la: had anti-FIV activity in CRFK cells (IC(50), 200 ng/ml) but not in feline thymocytes (IC(50), >2.5 mu g/ml). When primary FIV isolates were evaluated for their drug susceptibility in feline thymocytes, the bicyclams AMD3100 and its Zn(2+) complex, AMD3479, inhibited all six primary isolates at equal potency. The marked susceptibility of FN to the bicyclams suggests that FIV predominantly uses feline CXCR4 for entering its target cells.